A nanoparticle-incorporated STING activator enhances antitumor immunity in PD-L1-insensitive models of triple-negative breast cancer.

Abstract

Triple-negative breast cancer (TNBC) has few therapeutic options, and alternative approaches are urgently needed. Stimulator of IFN genes (STING) is becoming an exciting target for therapeutic adjuvants. However, STING resides inside the cell, and the intracellular delivery of CDNs, such as cGAMP, is required for the optimal activation of STING. We show that liposomal nanoparticle-delivered cGAMP (cGAMP-NP) activates STING more effectively than soluble cGAMP. These particles induce innate and adaptive host immune responses to preexisting tumors in both orthotopic and genetically engineered models of basal-like TNBC. cGAMP-NPs also reduce melanoma tumor load, with limited responsivity to anti-PD-L1. Within the tumor microenvironment, cGAMP-NPs direct both mouse and human macrophages (M), reprograming from protumorigenic M2-like phenotype toward M1-like phenotype; enhance MHC and costimulatory molecule expression; reduce M2 biomarkers; increase IFN-γ-producing T cells; augment tumor apoptosis; and increase CD4+ and CD8+ T cell infiltration. Activated T cells are required for tumor suppression, as their depletion reduces antitumor activity. Importantly, cGAMP-NPs prevent the formation of secondary tumors, and a single dose is sufficient to inhibit TNBC. These data suggest that a minimal system comprised of cGAMP-NP alone is sufficient to modulate the tumor microenvironment to effectively control PD-L1-insensitive TNBC.

• Authors: Ning Cheng, Rebekah Watkins-Schulz, Robert D Junkins, Clément N David, Brandon M Johnson, Stephanie A Montgomery, Kevin J Peine, David B Darr, Hong Yuan, Karen P McKinnon, Qi Liu, Lei Miao, Leaf Huang, Eric M Bachelder, Kristy M Ainslie, Jenny P-Y Ting
• Journal: JCI insight (JCI Insight) Vol. 3 Issue 22 (11 15 2018) ISSN: 2379-3708 [Electronic] United States
• PMID: 30429378 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• B7-H1 Antigen
• CD274 protein, human
• Interferon Type I
• Liposomes
• Membrane Proteins
• Nucleotides, Cyclic
• STING1 protein, human
• Sting1 protein, mouse
• cyclic guanosine monophosphate-adenosine monophosphate

Topics

• Animals
• B7-H1 Antigen (immunology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Immunity, Innate (drug effects)
• Immunotherapy
• Interferon Type I (genetics)
• Liposomes
• Macrophages (immunology)
• Melanoma, Experimental (genetics, immunology, therapy)
• Membrane Proteins (genetics)
• Mice
• Mice, Inbred C57BL
• Nanoparticles (therapeutic use)
• Neoplasm Transplantation
• Nucleotides, Cyclic (administration & dosage, pharmacology)
• T-Lymphocytes (immunology)
• Triple Negative Breast Neoplasms (genetics, immunology, therapy)